4ZDZ

Saccharomyces cerevisiae CYP51 (Lanosterol 14-alpha demethylase) Y140F mutant complexed with fluconazole

Summary for 4ZDZ

• Entry DOI: 10.2210/pdb4zdz/pdb
• Related: 4K0F 4LXJ 4WMZ 4ZDY 4ZE0 4ZE1 4ZE2 4ZE3
• Descriptor: Lanosterol 14-alpha demethylase, PROTOPORPHYRIN IX CONTAINING FE, 2-(2,4-DIFLUOROPHENYL)-1,3-DI(1H-1,2,4-TRIAZOL-1-YL)PROPAN-2-OL, ... (4 entities in total)
• Functional Keywords: cyp51, oxidoreductase-oxidoreductase inhibitor complex, resistance mutation, oxidoreductase/oxidoreductase inhibitor
• Biological source: Saccharomyces cerevisiae (strain YJM789) (Baker's yeast)
• Total number of polymer chains: 1
• Total formula weight: 62791.97

Authors

Sagatova, A.,Keniya, M.V.,Wilson, R.K.,Tyndall, J.D.A.,Monk, B.C. (deposition date: 2015-04-20, release date: 2016-03-30, Last modification date: 2024-03-13)

Primary citation

Sagatova, A.A.,Keniya, M.V.,Wilson, R.K.,Sabherwal, M.,Tyndall, J.D.,Monk, B.C.
Triazole resistance mediated by mutations of a conserved active site tyrosine in fungal lanosterol 14 alpha-demethylase.
Sci Rep, 6:26213-26213, 2016

PubMed Abstract: Emergence of fungal strains showing resistance to triazole drugs can make treatment of fungal disease problematic. Triazole resistance can arise due to single mutations in the drug target lanosterol 14α-demethylase (Erg11p/CYP51). We have determined how commonly occurring single site mutations in pathogenic fungi affect triazole binding using Saccharomyces cerevisiae Erg11p (ScErg11p) as a target surrogate. The mutations Y140F/H were introduced into full-length hexahistidine-tagged ScErg11p. Phenotypes and high-resolution X-ray crystal structures were determined for the mutant enzymes complexed with short-tailed (fluconazole and voriconazole) or long-tailed (itraconazole and posaconazole) triazoles and wild type enzyme complexed with voriconazole. The mutations disrupted a water-mediated hydrogen bond network involved in binding of short-tailed triazoles, which contain a tertiary hydroxyl not present in long-tailed triazoles. This appears to be the mechanism by which resistance to these short chain azoles occurs. Understanding how these mutations affect drug affinity will aid the design of azoles that overcome resistance.

PubMed: 27188873
DOI: 10.1038/srep26213

Experimental method

X-RAY DIFFRACTION (2.3 Å)